It is known that dopamine D2 agonists such as apomorphine or rotigotine may in principle be used to treat morbus Parkinson and other diseases for which an increase of the dopamine level is beneficial such as the restless leg syndrome (RLS). However, due to the very high first-pass effect of most of these dopamine agonists and the problem that many Parkinson patients develop some kind of drug tolerance against these drugs, the development of a safe and effective pharmaceutical formulation by which controlled amounts of drug can be administered is far from trivial.
Rotigotine (5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol, sometimes also designated as N-0923) and its pharmaceutically acceptable salts have been previously administered to patients mainly in the form of transdermal delivery systems (see e.g. WO 94/07468, WO 99/49852, EP-A-1 256 339). However, there was also at least one attempt of an intranasal administration of this drug (Swart et al., Pharmaceutical Sciences 1995, 1: 437-440). Swart et al. administered a solution of rotigotine hydrochloride in a 1:1 mixture of polyethylenglycol (PEG) 400 and water to male Albino Wistar rats. While they observed an improved bioavailability of rotigotine after buccal, nasal or rectal administration compared with oral dosing in the rat, they also observed that the bioavailability for the nasal dosing was “somewhat disappointing” when compared with the results described for other lipophilic drugs. Swart et al. suggested that the relatively low bioavailability they observed may be explained by a low absorption or rapid metabolic conversion of the drug in the nasal mucosa. These authors further stated that as of 1995 no information was available about the influence of rotigotine on the ciliary function of the nasal mucosa. In their view, nasal medication may change or even destroy the epithelial cells, with the recovery taking a few hours to a few months depending on the agent (Van Donk et al., Rhinology 18: 93-104).
In view of this rather discouraging report, it is perhaps not very surprising that the nasal administration of rotigotine does not seem to have been further attempted in the years after 1995 until the present invention was made. The state of information on the influence of rotigotine on the ciliary function of the nasal mucosa remained basically unchanged since these days.
US-A-2003-0,124,191 discloses a pharmaceutical composition in powder form that is intended for administration through the mucosa. A large variety of active ingredients including, among many others, rotigotine may be used as the active principle of this formulation which may further contain wetting agents, binding agents, diluents, penetration enhancers and other ingredients. The penetration enhancers of this reference include, among many others, cyclodextrins. The administration routes described in this application are again multifold and comprise administration through the buccal mucosa, the nasal mucosa, the vaginal mucosa and sublingual administration. However, this reference does not specifically disclose an intranasal formulation of rotigotine and provides no teaching as to requirements and the necessary/suitable ingredients of such an intranasal formulation.
Apomorphine is a drug that shares certain functional features with rotigotine but is structurally different. Like rotigotine, apomorphine is a dopamine agonist and has therefore been used to treat various dopamine-related disorders, including morbus Parkinson. The nasal administration of apomorphine has also been tried. For example, WO 94/22445 describes pharmaceutical compositions for intranasal administration of apomorphine, morphine and dihydroergotamine. These drugs can be used in combination with saccharides or higher sugar alcohols.
J. Duarte et al. describe aspects of intranasal apomorphine in Parkinson's Disease in J. Pharmacol. Technol. 11:226-228 (1995). This report states on the one hand that intranasal administration of apomorphine is a comfortable and effective alternative to subcutaneous administration but on the other hand also mentions that one patient developed a nasal vestibulitis (“troublesome rhinitis”) during chemical trials. While this patient could continue apomorphine therapy, doubts do remain of the general suitability of this therapy form when account is taken of the fact that only four patients participated in this study. A very similar report on such side effects is given in Ned Tijdschr Geneeskd 1992; 136, nr 14, p. 702. The authors of this reference suspect that apomorphine may bind as a hapten to proteins in the nasal mucosa and thus evoke an allergic reaction. Thus, even in the case of apomorphine, the problem of finding a safe (non-allergenic) and effective intranasal medication cannot be considered as having been solved satisfactorily.
More recently, the same findings with liquid intranasal formulations of apomorphine were confirmed again by Djupesland et al. in PFO Magazine, June/July 2002. These authors stated that while administration of liquid intranasal apomorphine has been shown to be effective in Parkinson's Disease, local side effects in the form of nasal crusting, inflammation and infection have been evident. In addition apomorphine was found to be subject to rapid oxidation in solution. To overcome these problems, a nasal-powder approach was developed.